Hedgehog-mediated regulation of PPARc controls metabolic patterns in neural precursors and shh-driven medulloblastoma Journal Article

   

Authors:	Bhatia, B.; Potts, C. R.; Guldal, C.; Choi, S.; Korshunov, A.; Pfister, S.; Kenney, A. M.; Nahle, Z. A.
Article Title:	Hedgehog-mediated regulation of PPARc controls metabolic patterns in neural precursors and shh-driven medulloblastoma
Abstract:	Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor progression, in an E2F1- and FASN-dependent manner.Here, we showthat the nutrient sensor PPARc is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposedmedulloblastoma cellsof- origin, Shh stimulation elicits a marked induction of PPARc alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARc expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARc and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival ofmedulloblastomabearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional regulator define a novel mechanismthrough which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh E2F1 PPARγ axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPARc downstreamof Shh as a global therapeutic target in hedgehogdependent and/or Rb-inactivated tumors. © The Author(s) 2012.
Keywords:	controlled study; unclassified drug; dna-binding proteins; nonhuman; cell proliferation; ki-67 antigen; mouse; metabolism; animals; mice; animal tissue; cell death; cerebellum; cells, cultured; sonic hedgehog protein; animal experiment; animal model; basic helix-loop-helix transcription factors; membrane proteins; in vivo study; neural stem cell; mice, inbred c57bl; time factors; mice, transgenic; transcription factors; transduction, genetic; gene expression regulation, neoplastic; enzyme inhibitors; brain development; medulloblastoma; carrier proteins; positron-emission tomography; animals, newborn; ex vivo study; cell cycle regulation; retinoblastoma protein; neural stem cells; sonic hedgehog; cerebellar neoplasms; peroxisome proliferator activated receptor gamma; ppar gamma; cell metabolism; neuropeptides; glucose transport; glycolysis; transcription factor e2f1; anilides; thyroid hormones; metabolic regulation; glucose metabolism; e2f1 transcription factor; glucose transporter 4; tumor metabolism; azo compounds; hexokinase; pyruvate kinase; hexokinase 2; ppar?; pyruvate kinase m2; cerebellar granule neural precursor; hedgehogs
Journal Title:	Acta Neuropathologica
Volume:	123
Issue:	4
ISSN:	0001-6322
Publisher:	Springer
Date Published:	2012-04-01
Start Page:	587
End Page:	600
Language:	English
DOI:	10.1007/s00401-012-0968-6
PROVIDER:	scopus
PMCID:	PMC3306783
PUBMED:	22407012
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84862799616&partnerID=40&md5=e32443a1f1b77042a8aea775bfd27cac
Notes:	--- - "Export Date: 1 August 2012" - "CODEN: ANPTA" - "Source: Scopus"